Zinc: What is its relevance to type 1 diabetes?
Authored by UF PathLabs' Endocrinology Unit Director William Ernest Winter, M.D.
Taken directly from a recent review by Fukada and Kambe1
"(Zinc) plays indispensable roles in multifarious cellular processes, affecting the expression and activity of a variety of molecules, including transcription factors, enzymes, adapters, channels, growth factors, and their receptors."
The newest autoantibody determination to enter the clinical realm of type 1 diabetes testing is the detection of autoantibodies against the type 8 zinc transporter (ZnT8)2. This transporter moves zinc into insulin-containing granules in the beta cells of the islets of Langerhans.
Autoantibodies to ZnT8 (termed "ZnT8A") are frequently found at the onset of type 1 diabetes2; however, the question arises:
"What is the value of ZnT8A testing when autoantibodies can be detected against the islet cell cytoplasm (ICA), glutamic acid decarboxylase (GADA), insulin (IAA) and the insulinoma-2 autoantigen (IA-2A)?"
The answer to this question is threefold:
New-onset patients with clinically suspected type 1 diabetes, who are negative for GADA, IA-2A and IAA, can be positive for ZnT8A, affirming an autoimmune etiology for a patient's diabetes. In a recent study, 14 percent of new-onset patients negative for GADA, IA-2A and IAA were positive for ZnT8A3.
In the detection of latent autoimmune diabetes of adulthood (LADA), ZnT8A are nearly as common as GADA. In a 2012 study from Trabucchi et al.4, the frequencies of GADA and ZnT8A in patients with adult-onset diabetes were, respectively, 7.7 and 7.0 percent; however, more meaningful is that many patients were positive for ZnT8A and negative for GADA. Adding ZnT8A to GADA testing will increase the yield of detection of LADA by about 60 percent. In other words, the frequency of LADA defined by the presence of GADA alone is 12.5 percent in adult-onset subjects with diabetes; however, the frequency of LADA rises to 20 percent when ZnT8A is added to GADA testing.
- Finally, in type 1 diabetes patients who have received a pancreas transplant, the presence of ZnT8A (as well as GADA and IA-2A), predict graft failure5. This is not good news for the patient or the transplant team; however, the recognition of such autoantibodies may allow the transplant team to identify patients who may require more vigorous immunosuppression to prevent a re-occurrence of beta-cell autoimmunity with subsequent destruction of the transplanted beta cells.
Testing for ZnT8A is now available from our CAP-accredited, CLIA-certified Endocrine Autoantibody Laboratory at UF PathLabs.
Fukada T, Kambe T. Molecular and genetic features of zinc transporters in physiology and pathogenesis. Metallomics. 2011 Jul;3(7):662-74.
Wenzlau JM, Juhl K, Yu L, Moua O, Sarkar SA, Gottlieb P, Rewers M, Eisenbarth GS, Jensen J, Davidson HW, Hutton JC. The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17040-5.
Vermeulen I, Weets I, Asanghanwa M, Ruige J, Van Gaal L, Mathieu C, Keymeulen B, Lampasona V, Wenzlau JM, Hutton JC, Pipeleers DG, Gorus FK; Belgian Diabetes Registry. Contribution of antibodies against IA-2β and zinc transporter 8 to classification of diabetes diagnosed under 40 years of age. Diabetes Care. 2011 Aug;34(8):1760-5.
Trabucchi A, Faccinetti NI, Guerra LL, Puchulu FM, Frechtel GD, Poskus E, Valdez SN. Detection and characterization of ZnT8 autoantibodies could help to screen latent autoimmune diabetes in adult-onset patients with type 2 phenotype. Autoimmunity. 2012 Mar;45(2):137-42.
- Occhipinti M, Lampasona V, Vistoli F, Bazzigaluppi E, Scavini M, Boggi U, Marchetti P, Bosi E. Zinc transporter 8 autoantibodies increase the predictive value of islet autoantibodies for function loss of technically successful solitary pancreas transplant. Transplantation. 2011 Sep 27;92(6):674-7.